1. Field of the Invention
The invention relates generally to drug delivery systems, and more specifically to a method and apparatus for in situ drug delivery for use in distraction osteogenesis.
2. Background Discussion
Distraction osteogenesis (DO) is an important technique for bone restoration. The procedure was pioneered by Dr. Gavril Ilizarov. The fundamental technical principle underlying the procedure is that by using a corticotomy to cut the cortex of a bone while maintaining the periosteal cover, an internal or external fixation device may be used to gradually separate the ends of the bone sections during the distraction phase of the process so as to lengthen the bone healing callus. In effect, it is a method of stretching existing bone by fostering growth in the gap between the separated bone sections. When the desired amount of growth or increased bone length or shape is achieved, the bones are allowed to continue healing during a consolidation phase. However, if the speed of the distraction is excessively fast, a nonunion can occur. Conversely, if the speed of distraction is too slow, the corticotomy can heal requiring a secondary corticotomy. Clinically, most fixators are distracted at a specific rate to ensure proper bone lengthening while preventing premature fusion. Once the desired degree of lengthening is achieved, most experts recommend a consolidation period of at least twice as long as the lengthening period.
Distraction osteogenesis can be used for a variety of indications including congenital deformities, traumatic injuries, infection, and tumors. Traditionally, distraction osteogenesis of the extremities has been performed with a ring external fixator with fine wires or half pins in the long bones. However, the indications for this procedure have expanded, particularly to include procedures in craniofacial surgery. A number of advances have been achieved in this area including the use of submergible distractors that can be placed under the skin, such as the implantable plate for distracting mandibular bone segments as, disclosed by Chin, U.S. Pat. No. 5,810,812.
Another recent innovation involves the use of plates attached to the bone for distraction osteogenesis, as disclosed by Elsalanty, WO 2005/086920. Others have described the use of bioabsorbable fixation foot plates connected with a telescoping rod for use in distraction osteogenesis, such as the apparatus described by Buchbinder, U.S. Pat. No. 6,293,947 B1.
Additional refinements of telescopic distraction osteogenesis systems have been proposed by Kourtis, EP 1 016 381 A1, and by Walker, U.S. Pat. No. 5,902,304.
One of the major obstacles to widespread use of distraction osteogenesis, particularly in the long bones, is the extensive period of time required for consolidation of the regenerated bone. The best strategy currently known for addressing this problem has been the use of drug delivery to the site of the distraction. A number of therapeutic agents and delivery methods have been developed to achieve this goal. Pharmacological agents employed to this end include, among others, growth factors and morphogens. The most widely accepted agent is bone morphogenic protein (BMP), which is routinely used in spinal fusion as well as in certain open extremity fractures.
Cheung et al studied the effect of increased distraction rate in a New Zealand White Rabbit mandibular distraction model with the addition of recombinant human BMP (rhBMP-2). Kim et al. have shown that in a dog model of mandibular distraction osteogenesis, BMP leads to substantially more bone than control when implanted at the end of the distraction period. Both of these studies employed a one-time delivery of BMP, and thus shed no light on whether additional delivery of BMP would affect the outcome.
Another strategy published by Ashinoff et al, involves the use of an adenovirus containing the gene for BMP-2. This virus was implanted into the distraction zone in a rat model of mandibular distraction osteogenesis at the end of the distraction period. The researchers found a significantly higher volume of bone in this group than in the control group. The advantage of this technique is the potential for longer drug exposure of the distraction zone resulting from the viral vector. At both 2 and 4 weeks of the consolidation period, they noted increased bone volumes in the BMP group. However at the 8 week mark, there was no difference in the mechanical strength between the BMP and control groups.
Angiogenic factors such as vascular endothelial growth factor (VEGF) provide yet another strategy to enhance bone regeneration speed and thereby to minimize the treatment duration in DO. Hu et al have shown that endogenous levels of VEGF are upregulated during the distraction process. Casap et al analyzed the effect of VEGF in a model of periosteal distraction osteogenesis whereby the periosteum is distracted to form new bone. In a rabbit model, they compared the effect of daily injections of VEGF for four days during the distraction process to control periosteal distraction. They found a statistically significant increase in bone volume using micro-computed tomography analysis in the VEGF group.
In spite of these remarkable results, the ability to regularly and repeatedly deliver drugs to the site of distraction osteogenesis remains an ongoing challenge. Grayson et al. have developed a device for drug delivery during DO using a cannulated pin system. (see Grayson, B. H., et al, Development of a device for the delivery of agents to bone during distraction osteogenesis, J Craniofacial Surg. 2001: 12(1):19-25.) India ink was injected into the pins in a canine mandibular DO model. The ink spread radially outward from the pins on visual examination and could be found within the regenerated bone under histological (microscopic) evaluation.
Konas, WO 2008/030201 A1, discloses a method for drug delivery with a internally mounted piston distractor. The distractor releases drug agents through the movements of the distractor and the rotation of a rod, which are transmitted to a piston inserted in a drug container. This leads to an incremental drug release during the distraction process.
However, there are still several challenges present in delivering constant amounts of drug at the site of bone distraction. Strategies to address this problem include the use of drug eluting pins, osmotic pumps, and multiple injections into the site. The present invention provides a device and method for applying any drug to the distraction site mechanically.
The foregoing patents and other publications reflect the current state of the art of which the present inventor is aware. Reference to, and discussion of, these publications is intended to aid in discharging Applicant's acknowledged duty of candor in disclosing information that may be relevant to the examination of claims to the present invention. However, none of the above-indicated publications disclose, teach, suggest, show, or otherwise render obvious, either singly or when considered in combination, the invention described and claimed herein.